Water in different forms is the most important raw material in
pharmaceutical production; quality problems of the purified water are the
most frequent cause for the recall of parenterals. In order to ensure a
GMP-compliant water quality, special attention should be given to the
facilities for the manufacture of pharmaceutical water on the one hand and
the pipes for the distribution of this water on the other hand. During the
past years there has been a rapid development in the design of
pharmaceutical piping systems.

We have taken this as an opportunity to
have a close look at the warning letters issued by the FDA during the past
years. In the following we have listed the original citations for the most frequently
criticised points.

1) Dead Legs

Dead legs were observed in the system and there is no temperature
control on the storage tank located outside of the building.

Failure to ensure that equipment used in the manufacture, processing,
packing or holding of drug products is of appropriate design, adequate size,
and suitably located for its intended use [211.63]. For example, you have
not validated the performance of manufacturing equipment, including a lack
of installation qualification, operation qualification and performance
qualification of your purified water system. Our investigator observed 4
dead legs associated with this water system.

In addition, cross connections and dead legs were observed with the
plumbing for the alfalfa soak tanks, the chlorinator for the spray, water
holding tanks is not maintained, specifically, the filter was noted to be
completely encrusted and the chlorinator was not working, mold was observed
on shelves and walls in the alfalfa grow room, there is no pest control
program in place, and product is packed and held under unshielded
fluorescent lights.

The plumbing system included defects that could contribute contamination
to the drug product. For example:

There were multiple significant design deficiencies such as dead legs of
various lengths, throughout the WFI system.

There were no piping and instrumental diagrams for the WFI or purified
water system.

WFI frequently fails conductivity due to system shut down.

The purified water system was observed to have sagging lines and dead
legs, is inadequately maintained, and use points are insufficiently tested
and controlled.

The following deviations relating to the watering point were observed
during the inspection:

No backflow preventer device on the water piping system.

The potable water hose was not capped.

There was an accumulation of dust on the floor of the potable water
cabinet.

Lack of any piping or instrument drawings of the deionized water or the
recently modified water system for the purposes of system maintenance,
monitoring and operation.

2) Insufficient Documentation

There was insufficient data to demonstrate that the purified water system
was capable of providing water which consistently met chemical and
microbiological specifications. Critical attributes of the system and
sampling and testing schedules were not outlined; daily sampling after each
phase of the system was never conducted; and there were no written sampling
procedures. In addition, grooved, flexible piping was used to transfer
purified water from the DI beds to the holding tank. There was no data to
show that this piping could be adequately sanitized.

The recirculating loop description provided via diagram fails to document
any temperature considerations or flow rates for the loop.

Written procedures do not include passivation of the water system in the
event that additional welding or modifications are performed.

3) Sampling

Water for Injection (WFI) is not sampled in the same manner as it is used
in production

4) Preventive Maintenance and Calibration

The current Piping and Instrumentation Diagram for the equipment could
never be located during the inspection. The piping configuration for the
rinse Water for Injection (WFI) included a large dead leg due to the
presence of an inverted filter housing which is not drained after use.
Several valves and the sampling port were not physically labeled. In
addition, several leaking valves and fittings were noted on the WFI piping.
These valves were not part of the preventative maintenance program at the
firm.

Thermometers which are used to monitor the temperature of the WI system
are not calibrated.

5) Equipment Design

Failure to ensure that equipment used in the manufacture, processing,
packing, or holding of a drug product is of appropriate design and adequate
size to facilitate operations for its intended use [21 CFR 211.63], in that
the Water for Injection (WFI) system is inadequately designed. For example:

sections of copper piping and flexible silicon tubing are not sloped in a
fashion to facilitate adequate draining

piping and equipment couplings used in the WFI system have threaded
unions.

6) Operation, Monitoring and Measures in Case of
Deviations

Failure to adequately monitor, investigate and take action on utility
design features and utility malfunctions which could have an adverse effect
on the purity and quality of sterile or non-pyrogenic bulk pharmaceuticals.
For example:

Ball valves, which are not considered to be sanitary, were used in the
connectors to attach hoses from the Low- Endotoxin Water System to the
equipment used to manufacture Piperacillin Monohydrate.

Incidents of failures of the resistivity meters, leaks and low pressure
in the Low Endotoxin Water System were not investigated to determine their
effect on the bacteriological quality of the water used for production of
Piperacillin Monohydrate.

Containers used to hold sterile water for injection (WFI) for final
rinsing of vials are not sterilized or monitored for presence of microbes.

Author:
Harald Martin
CONCEPT HEIDELBERG

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